A specific enzyme, leucokinase, that is located in the outer membrane of the neutrophils, spilits leucocinin, a leucophilic fraction of immunoglobulin G (IgG) and produces a phagocytosis-stimulating tetrapeptide (Najjar V. A. and Nishioka K., 1970, Nature 228, pp. 672-673). That tetrapeptide was subsequently named “tuftsin” (Najjar V. A. and Nishioka K., 1970, Nature 228, pp. 672-673; Sieminon I. Z. and Kluczyk A., 1999, Peptides 20, pp. 645-674). Tuftsin (Thr-Lys-Pro-Arg) is a 289-292 sequence in the CH2 domain of the Fc subunit of human IgG1 heavy (H) chain. It was originally found that tuftsin stimulates phagocytosis after binding to polymorphonuclear cells (Constantopoulos A. and Najjar V. A., 1972, Cyobios. 6, pp. 97-100; Najjar V. A. and Constantopoulos A. A., 1972, J. Reticulendothel. Soc. 12, pp. 197-215; Najjar V. A., 1979, Clin. Wochenschr. 57, pp. 751-756; Najjar V. A., 1980, Adv. Exp. Med. Biol. 121 A, 131-147; Najjar V. A., 1983, Ann. NY Acad. Sci. 419, pp. 1-11). Subsequently, tuftsin was also shown to stimulate the phagocytosis activity of monocytes-macrophages (Coleman D. L., 1986, Eur. J. Clin. Microbiol. 5, pp. 1-5). Potentially, tuftsin could be used as a drug component to increase phagocytosis activities. However, the drawback is that tuftsin activity is very low demanding its high concentrations in blood circulation. Another drawback is that half-lives of linear peptides in blood are short.
In 1980 the existence of a β-endorphin-like sequence in CH3 domain of the Fc subunit of human IgG1-4H-chain was reported (Julliard J. H. et al., 1980, Science 208, pp. 183-185). To isolate ACTH and β-endorphin from human placenta, the authors used immobilized antibodies to these hormones as affinity absorbents. A 50 kDa protein was thereby isolated and found to be an H-chain of IgG. Elucidation of the origin of such an effect led to the discovery of ACTH- and β-endorphin-like sequences in the H-chain. It was found that the human IgG1 H-chain fragment 364-377 (SLTCLVKGFYPSDI (SEQ ID NO:1); see FIG. 1) was 40% homologous to βendorphin fragment 10-23 (SQTPLVTLFKNAII (SEQ ID NO:2)). An artificial peptide (14 amino acid residues) corresponding to the β-endorphin-like human IgG1 sequence was synthesized and found to interact with rat brain receptors for β-endorphin (Houck J. C. et al., 1980, Science 207, 78-80). Our group synthesized a decapeptide SLTCLVKGFY(SEQ ID NO:3) (termed immunorphin) corresponding to the human IgG1 H-chain sequence 364-37. It was demonstrated to compete with [125I]β-endorphin for high-affinity receptors on murine peritoneal macrophages (Ki=2.5 nM; Zav'yalov V. P. et al., 1996, Immun. Lett. 49, 21-26). Later on it was also demonstrated to compete with [125I]β-endorphin for high-affinity receptors on T lymphocytes from the blood of healthy donors (Ki=0.6 nM). Tests of the specificity of the receptors revealed that they are insensitive to an antagonist of opioid receptors naloxone and [Met5]enkephalin, i.e. they are non-opioid receptors. The displacement assays demonstrated that pentapeptide VKGFY(SEQ ID NO:4), termed hereinafter as pentarphin, was the shortest immunorphin fragment, capable of inhibiting [125I]β-endorphin binding to non-opioid receptors on murine macrophages (Ki=12 nM) and human T lymphocytes (Ki=15 nM). According to the present invention, the primary effect of pentarphin, following binding to specific cell surface receptors, consists of the stimulation of the functions of macrophages and T lymphocytes.